Self-Assembly of Extracellular Vesicle-like Metal–Organic Framework Nanoparticles for Protection and Intracellular Delivery of Biofunctional Proteins

Abstract

The intracellular delivery of biofunctional enzymes or therapeutic proteins through systemic administration is of great importance in therapeutic intervention of various diseases. However, current strategies face substantial challenges owing to various biological barriers, including susceptibility to protein degradation and denaturation, poor cellular uptake, and low transduction efficiency into the cytosol. Here, we developed a biomimetic nanoparticle platform for systemic and intracellular delivery of proteins. Through a biocompatible strategy, guest proteins are caged in the matrix of metal-organic frameworks (MOFs) with high efficiency (up to ∼94%) and high loading content up to ∼50 times those achieved by surface conjunction, and the nanoparticles were further decorated with the extracellular vesicle (EV) membrane with an efficiency as high as ∼97%. In vitro and in vivo study manifests that the EV-like nanoparticles can not only protect proteins against protease digestion and evade the immune system clearance but also selectively target homotypic tumor sites and promote tumor cell uptake and autonomous release of the guest protein after internalization. Assisted by biomimetic nanoparticles, intracellular delivery of the bioactive therapeutic protein gelonin significantly inhibits the tumor growth in vivo and increased 14-fold the therapeutic efficacy. Together, our work not only proposes a new concept to construct a biomimetic nanoplatform but also provides a new solution for systemic and intracellular delivery of protein.

Modulating the Biofunctionality of Metal–Organic‐Framework‐Encapsulated Enzymes through Controllable Embedding Patterns

“…[10,11,56,57] Furthermore,i ncreasing efforts were devoted to construct biomacromolecule@nanoZIF-8 intracellular delivery systems for protein-and gene-based theranostics. [25,[58][59][60] These applications receive more and more attention because of the high loading efficiency and protecting effect of ZIF-8, and the convenient de novo synthesis process.H erein, we highlighted the importance of the embedding patterns for facilitating and preserving the biofunctionality of abiomacromolecule encapsulated within ZIF-8. Importantly,o ur work demonstrated that the embedding patterns can be controlled by chemical modification of the amino acids of the protein that enabled the modulation of the biofunctionality of proteins@ZIF-8.…”

Nanobiohybrids: Materials approaches for bioaugmentation

“…(F) Poly(3,4-ethylenedioxythiophene) (PEDOT) infusion into leaves by a syringe (48). (G) Schematic illustration of the biomimetic EV-MOF protein nanoparticles and the intracellular delivery of proteins (78). (H) Schematic illustration of biomimetic crystallization of cytoprotective MOF coatings on living yeast cells (11).…”

“…(K) Illustration of MOF formation inside of living plants (15). Reproduced with permissions from the Royal Society of Chemistry (22), American Chemical Society (78,86) Springer Nature (39), Wiley-VCH (11,15,44,62), National Academy of Sciences (80), and American Association for the Advancement of Science (48).…”

“…In a very recent work, Zheng and co-workers interfaced lipid vesicles with protein/MOF particles ( Fig. 2G) (78). By mixing the extracellular vesicles (e.g., exosomes) with the protein/ZIF-8 particles under ultrasonication and then extrusion, the surface of the MOFs was decorated with the lipid bilayer membrane (78).…”

Materials for Immunotherapy

“…The hydrides of Eu 3+ and GMP dissociated under acidic conditions, which accelerated protein escape from endosomal and lysosomal compartments to enhance antigen cross‐presentation and thus CTL stimulation. Zheng and co‐workers developed a MOF‐based nanocarrier decorated with extracellular vesicle membranes . The authors encapsulated protein (gelonin) into MOF (ZIF‐8) matrices with high loading efficiencies and coated the MOF particles with extracellular vesicle membranes, preventing protein degradation by proteases and enabling significant inhibition of tumor growth.…”